5eeq

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==Grb7 SH2 with the G7-B1 bicyclic peptide inhibitor==
==Grb7 SH2 with the G7-B1 bicyclic peptide inhibitor==
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<StructureSection load='5eeq' size='340' side='right' caption='[[5eeq]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
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<StructureSection load='5eeq' size='340' side='right'caption='[[5eeq]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5eeq]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EEQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EEQ FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5eeq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EEQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EEQ FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
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<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=48V:{[(2R)-2,3-DIAMINO-3-OXOPROPYL]SULFANYL}ACETIC+ACID'>48V</scene>, <scene name='pdbligand=73C:(2~{S})-2-AZANYL-3-BUTOXY-PROPANOIC+ACID'>73C</scene></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=48V:{[(2R)-2,3-DIAMINO-3-OXOPROPYL]SULFANYL}ACETIC+ACID'>48V</scene>, <scene name='pdbligand=73C:(2~{S})-2-AZANYL-3-BUTOXY-PROPANOIC+ACID'>73C</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5eel|5eel]]</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5eeq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eeq OCA], [https://pdbe.org/5eeq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5eeq RCSB], [https://www.ebi.ac.uk/pdbsum/5eeq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5eeq ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5eeq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eeq OCA], [http://pdbe.org/5eeq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5eeq RCSB], [http://www.ebi.ac.uk/pdbsum/5eeq PDBsum]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/GRB7_HUMAN GRB7_HUMAN]] Adapter protein that interacts with the cytoplasmic domain of numerous receptor kinases and modulates down-stream signaling. Promotes activation of down-stream protein kinases, including STAT3, AKT1, MAPK1 and/or MAPK3. Promotes activation of HRAS. Plays a role in signal transduction in response to EGF. Plays a role in the regulation of cell proliferation and cell migration. Plays a role in the assembly and stability of RNA stress granules. Binds to the 5'UTR of target mRNA molecules and represses translation of target mRNA species, when not phosphorylated. Phosphorylation impairs RNA binding and promotes stress granule disassembly during recovery after cellular stress (By similarity).<ref>PMID:10893408</ref> <ref>PMID:12021278</ref> <ref>PMID:12223469</ref> <ref>PMID:20622016</ref>
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[https://www.uniprot.org/uniprot/GRB7_HUMAN GRB7_HUMAN] Adapter protein that interacts with the cytoplasmic domain of numerous receptor kinases and modulates down-stream signaling. Promotes activation of down-stream protein kinases, including STAT3, AKT1, MAPK1 and/or MAPK3. Promotes activation of HRAS. Plays a role in signal transduction in response to EGF. Plays a role in the regulation of cell proliferation and cell migration. Plays a role in the assembly and stability of RNA stress granules. Binds to the 5'UTR of target mRNA molecules and represses translation of target mRNA species, when not phosphorylated. Phosphorylation impairs RNA binding and promotes stress granule disassembly during recovery after cellular stress (By similarity).<ref>PMID:10893408</ref> <ref>PMID:12021278</ref> <ref>PMID:12223469</ref> <ref>PMID:20622016</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The design of potent and specific peptide inhibitors to therapeutic targets is of enormous utility for both proof-of-concept studies and for the development of potential new therapeutics. Grb7 is a key signaling molecule in the progression of HER2 positive and triple negative breast cancers. Here we report the crystal structure of a stapled bicyclic peptide inhibitor G7-B1 in complex with the Grb7-SH2 domain. This revealed an unexpected binding mode of the peptide, in which the staple forms an alternative contact with the surface of the target protein. Based on this structural information, we designed a new series of bicyclic G7 peptides that progressively constrain the starting peptide, to arrive at the G7-B4 peptide that binds with an approximately 2-fold enhanced affinity to the Grb7-SH2 domain (KD = 0.83 muM) compared to G7-B1 and shows low affinity binding to Grb2-, Grb10- and Grb14-SH2 domains (KD &gt; 100 muM). Furthermore, we determined the structure of the G7-B4 bicyclic peptide in complex with the Grb7-SH2 domain, both before and after ring closing metathesis to show that the closed staple is essential to the target interaction. The G7-B4 peptide represents an advance in the development of Grb7 inhibitors and is a classical example of structure aided inhibitor development.
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Unexpected involvement of staple leads to redesign of selective bicyclic peptide inhibitor of Grb7.,Gunzburg MJ, Kulkarni K, Watson GM, Ambaye ND, Del Borgo MP, Brandt R, Pero SC, Perlmutter P, Wilce MC, Wilce JA Sci Rep. 2016 Jun 3;6:27060. doi: 10.1038/srep27060. PMID:27257138<ref>PMID:27257138</ref>
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==See Also==
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*[[Growth factor receptor-bound proteins 3D structures|Growth factor receptor-bound proteins 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5eeq" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Ambaye, N D]]
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[[Category: Homo sapiens]]
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[[Category: Watson, G M]]
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[[Category: Large Structures]]
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[[Category: Wilce, G M]]
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[[Category: Synthetic construct]]
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[[Category: Wilce, M C.J]]
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[[Category: Ambaye ND]]
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[[Category: Inhibitor]]
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[[Category: Watson GM]]
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[[Category: Sh2]]
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[[Category: Wilce GM]]
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[[Category: Signaling protein-inhibitor complex]]
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[[Category: Wilce MCJ]]
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[[Category: Staple]]
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Current revision

Grb7 SH2 with the G7-B1 bicyclic peptide inhibitor

PDB ID 5eeq

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